Tumor cytonemes, a new target for tumor suppression

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 DESCRIPTION (provided by applicant): Recent progress in tumor biology has revealed that stromal cells - the non-transformed neighbors of tumor cells - play essential roles for tumor stem cells, tumor progression and metastasis. These roles involve communication between tumor and stromal cells, but the signals that are exchanged and the mechanism by which these signals move and elicit responses remain obscure. This is a proposal to build on our recent discovery that specialized organelles called cytonemes move and exchange signaling proteins between epithelial and mesenchymal cells in Drosophila - revealing that paracrine signaling in these normal contexts is mediated by cytonemes that make direct synaptic contacts between signaling cells. Importantly, we also identified mutant genetic conditions that compromised cytonemes and eliminated the contacts cytonemes normally make to mediate signaling, and showed that signaling was abrogated if cytonemes did not make direct synaptic contacts with target cells. All the paracrine signaling was cytoneme-dependent. We also tested the prediction that tumor cells communicate with stromal neighbors by a similar mechanism, and when we examined cells in a Drosophila tumor model, we detected cytonemes that extend from tumor cells to their normal neighbors. The presence of these organelles is consistent with the idea that they mediate signaling between tumor and stromal cells. The objective of the work proposed here is to investigate the role of cytonemes in tumorigenesis in Drosophila and mouse models. The goals are to identify where and in what form cytonemes are present, discover how cytonemes link tumor cells with their non-transformed neighbors, and determine whether cytoneme-mediated signaling is essential for the tumor growth. Based on previous studies, the likelihood that cytonemes are present and have essential roles in the vertebrate contexts is high. The proposed work may open a new avenue for controlling tumor growth, and by bringing this novel mechanism of cell-cell communication to the attention of the broader community of cancer biologists, it may alert them to the importance of cytoneme-mediated signaling and to the practicality of harnessing it for studies and therapy.